Methods and devices for improving breathing in patients with pulmonary disease

ABSTRACT

Methods, apparatus, and kits for enhancing breathing in patients suffering from chronic pulmonary obstructive disease are described. The methods and apparatus rely on increasing flow resistance to expiration in a manner which mimics “pursed lip” breathing which has been found to benefit patients suffering from this disease. In a first example, a device is implanted in a trachea or bronchial passage to increase flow resistance, preferably selectively increase resistance to expiration relative to inspiration. In a second embodiment, a mouthpiece is provided, again to increase resistance to expiration, preferably with a lesser increase in flow resistance to inspiration. In a third embodiment, the patient&#39;s trachea or bronchial passage is modified by the application of energy in order to partially close the lumen therethrough.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. patent application Ser. No. 12/014,060,filed on Jan. 14, 2008, which is a divisional of U.S. patent applicationSer. No. 10/827,073, filed on Apr. 19, 2004, now U.S. Pat. No.7,334,581, which is a continuation of Ser. No. 09/881,862, filed on Jun.14, 2001, now U.S. Pat. No. 6,722,360, which claims the benefit ofProvisional U.S. Patent Application No. 60/211,990, filed Jun. 16, 2000,the disclosures of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates generally to the field of pulmonology, andmore particularly to the field of chronic obstructive pulmonary disease.In this regard, the invention provides devices and methods that areuseful in improving breathing in patients with chronic pulmonarydisease.

Chronic obstructive pulmonary diseases (COPD) is both very common andincreasing in incidence. COPD is the fourth most common cause of deathin this country and the morbidity and mortality it causes continue toincrease.

COPD comprises chronic bronchitis and emphysema. In both chronicbronchitis and emphysema, airflow obstruction limits the patient's airflow during exhalation. COPD is a progressive disease characterized byworsening baseline breathing status over a period of many years withsporadic exacerbations often requiring hospitalization.

Typically, patients with COPD have extensive smoking histories; smokingis the major risk factor for development of COPD. Symptoms typicallybegin in the fifth decade of life with progression to dyspnea onexertion during the sixth and seventh decade. Early symptoms includeincreasing sputum production, and sporadic acute exacerbationscharacterized by increased cough, purulent sputum, wheezing, dyspnea,and fever. As the disease progresses, the acute exacerbations becomemore frequent. Late in the course of the disease, the patient maydevelop hypercapnea, bypoxemia, erlthrocytosis, cor pulmonale with rightheart failure, and edema.

Though both chronic bronchitis and emphysema lead to chronic obstructionleading to limitation in expiratory flow, the pathophysiology andclinical presentation of each disease are different. Chronic bronchitisis characterized by chronic cough with sputum production leading toobstructed expiration. Pathologically, there is mucosal and submucosaledema and inflammation and an increase in the number and size of mucusglands. Emphysema is characterized by destruction of the lung parenchymaleading to loss of elastic recoil, reduced tethering of airways, andobstruction to expiration. Pathologically, the distal airspaces areenlarged.

Management of COPD is largely medical and infrequently surgical.Initially, exercise and smoking cessation are encouraged. Medicationsincluding bronchodilators (including beta-agonists, anti-cholinergics,and theophylline) and anti-inflammatories are routinely prescribed butare by no means curative. Pulmonary rehabilitation is often prescribedand has been shown to improve quality of life and sense of well being.Long term oxygen is generally reserved for the more severely affectedpatients. Surgical options are limited and include lung volume reductionsurgery and lung transplantation. Both of these surgical options,because of associated morbidity, are infrequently performed.

One of the important components of the aforementioned pulmonaryrehabilitation is breathing retraining. This involves teaching thepatient new breathing techniques that reduce hyperinflation of the lungsand relieve expiratory airflow obstruction. One of the goals is ofcourse to reduce the level of dyspnea. Typically, these new breathingtechniques include diaphragmatic and pursed-lip breathing. This lattertechnique, pursed-lip breathing, involves inhaling slowly through thenose and exhaling through pursed-lips (as if one were whistling), takingtwice as long to exhale as to inhale. Most COPD patients instinctivelylearn how to perform pursed-lip breathing in order to relieve theirdyspnea.

The belief among the medical community is that by producing a proximalobstruction (pursing the lips), the effect is to splint open the distalairways that have lost their tethering. In other words, the affectedairways that would normally collapse upon themselves remain open whenthe patient breathes through pursed-lips.

Medical literature has confirmed the utility of pursed-lip breathing inCOPD patients. Specifically, it has been found that respiratory rate isreduced, tidal volumes are increased, and oxygen saturation is improved.All of these contribute to improved dyspnea on the part of the patient.The drawbacks of pursed-lip breathing are twofold. First, because itrequires conscious effort, the patient cannot breath through pursed lipswhile sleeping. As a result, the patient can still become hypoxic atnight and may develop pulmonary hypertension and other sequelae as aresult. Second, since the patient has to constantly regulate his ownbreathing, this interferes with his performing other activities.

Clearly, there is a need for a medical device and/or procedure thatmimics the effect of pursed-lip breathing without suffering from theabove drawbacks. As such, there is much interest in the development ofnew medical devices and methods for use in procedures for patients withCOPD.

SUMMARY OF THE INVENTION

The According to the present invention, there is a potentiallysignificant benefit for a patient who undergoes a simple procedure thatcreates an obstruction to expiratory airflow within the airways. Thereare several possible means of achieving the requisite expiratoryobstruction. A device capable of delivering energy (radiofrequency,ultrasound, microwave, laser, cryo) could be used to create a localizedscarring or area or stenosis in the appropriate location, most likely inthe trachea, main bronchi, or other conducting airways. The goal of thistreatment would be to create a proximal obstruction that would alleviatethe expiratory limitations caused by the collapse of the smaller distalairways. In COPD, inspiratory airflow is relatively unaffected, so thepresence of a fixed obstruction present during both phases of therespiratory cycle would not likely obstruct inspiratory airflow to anappreciable amount.

Another approach would be to implant a device into the airways (mostlikely the trachea or bronchi) that would create a similar obstruction.This device could either be composed of non-moving parts, or couldpartially obstruct the airway on expiration and not obstruct the airwayon inspiration. That is, the direction of the airflow would determine ifthe obstruction were present.

Such a device and or methods will mimic the positive benefits ofpursed-lip breathing, specifically the increase in tidal volume,decrease in respiratory rate, increase in oxygen saturation, andimprovement in patient dyspnea.

In a first aspect, the present invention will provide implantabledevices for use in the treatment of COPD. The implantable devices willusually comprise a frame which is implantable within a lung passageway,typically the trachea or a bronchial passage. The frame will include amechanism or other means for increasing flow resistance to expiration.In a simple embodiment, the flow resistance means will be a simple flowresistor that provides increased resistance to both inspiration andexpiration. In such cases, the flow resistor could be a simple platewhich is held within the lung passage and which occludes some portion ofthe luminal cross-sectional area. Preferably, however, the means willcomprise a flow resistor which selectively increases resistance toexpiration while minimally increasing flow resistance to inspiration. Itwill be appreciated that the frame could carry a variety of “one-wayvalve structures,” or other flow responsive elements which open toinspiration and close to expiration. Of course, when closing toexpiration, the means should not fully occlude the lung passage sincethe patient must still be able to exhale, albeit at a slower rate inorder to assure a more complete evacuation of the lungs.

In a second aspect, the present invention comprises a mouthpiece which auser may conveniently insert and remove depending on need. Themouthpiece will be adapted to fit in the mouth, typically being heldbetween the teeth in the upper and lower jaws. As with the earlierembodiment, the mouthpiece embodiment will increase flow resistance toexpiration. Usually, there will be a much lesser increase in resistanceto inspiration, although the presence of the mouthpiece will very likelylead to at least a minimal increase in flow resistance to inspiration.In the preferred embodiments, a variety of one-way valves, flaps, orother flow-responsive elements may be provided.

In a third aspect, the present invention provides methods for treatingpatients suffering from chronic obstructive pulmonary disease (COPD).The methods broadly comprise creating a resistance to expiratory flow ina lung passage, typically the trachea or a bronchial passage. Themethods may comprise use of any of the devices described above. Forexample, the flow resistance may be created by implanting a flowresistor, either one with a fixed flow resistance or one with a variableflow resistance, i.e., which is higher to expiration than inspiration.Alternatively, the flow resistance could be increased by modifying alung passage to decrease the available luminal area. Such methods willtypically comprise applying energy to a portion of the luminal wall,typically in the trachea or bronchial passage, so that the lumendecreases in response to the application of energy. In a first specificinstance, the energy can be applied in such a way that the wall isinjured and scar tissue forms to partially occlude the passage. In asecond instance, the energy can be applied under conditions which shrinkthe collagen in order to close the passage, but where minimal tissuedamage and injury response occur.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a three-dimensional view of a first embodiment of thesubject devices where the device is depicted in a first, retractedposition.

FIG. 2 provides a three-dimensional view of the device shown in FIG. 1,where the device is depicted in the deployed position with closure ofthe central valve.

FIG. 3 provides a three-dimensional view of the device shown in FIG. 1,where the device is depicted in deployed position with opening of thecentral valve in the downward direction.

FIG. 4 provides a three-dimensional view of the device shown in FIG. 1,where the device is depicted in a deployed position with deflection ofthe central valve in the upwards direction.

FIG. 5 provides a three-dimensional view of a second embodiment of thesubject devices in which the device is removable and fits within theoral cavity.

FIG. 6 provides a three-dimensional view of the device shown in FIG. 5,where the device is depicted during exhalation with closure of thevalve.

FIG. 7 provides a three-dimensional view of the device shown in FIG. 5,where the device is depicted during inhalation with inward opening ofthe valve.

FIG. 8 provides a three-dimensional view of the device shown in FIG. 5,where the device is depicted with outward deflection of the valve.

FIG. 9 is a top plan view of the rim and valve of FIGS. 1-4.

FIG. 10 is a cross-sectional view of the valve taken along lines 10-10of FIG. 9.

FIG. 11 is a side view of the valve when in a fully opened conditionresponsive to inspiration.

FIG. 12 is a side view of the valve when in a partially opened conditionresponsive to expiration of high pressure.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

Medical devices and methods for their use in improving breathing in COPDpatients are provided.

Before the subject invention is further described, it is to beunderstood that the invention is not limited to the particularembodiments of the invention described below, as variations of theparticular embodiments may be made and still fall within the scope ofthe appended claims. It is also to be understood that the terminologyemployed is for the purpose of describing particular embodiments, and isnot intended to be limiting. Instead, the scope of the present inventionwill be established by the appended claims.

It must be noted that as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referenceunless the context clearly dictates otherwise. Unless defined otherwiseall technical and scientific terms used herein have the same meaning ascommonly understood to one of ordinary skill in the art to which thisinvention belongs.

Devices

As summarized above, the subject devices are devices for use inimproving the breathing of patients with chronic obstructive pulmonarydisease. As such, the subject devices are devices designed to alter theair flow into and out of the lungs. A feature of the subject devices isthat they contain a means of obstructing air flow, specifically air flowduring the expiratory phase of the respiratory cycle.

As such, the subject devices consist of two main components, the firstis a means of anchoring the device to a certain location, the second ameans of regulating gas flow to and from the lungs.

In those embodiments where the anchoring means is by a plurality ofexpanding anchoring legs, these anchoring legs secure the devicetemporarily or permanently in the trachea or bronchi. These legs may bemade of a large number of materials, with the preference that the chosenmaterial have shape memory. That is, the legs would be expected tospring outward following deployment and thereby facilitate contact withthe surrounding tissues such as the trachea, bronchi, and otherrespiratory conduits.

In those embodiments where the anchoring means is a removablemouthpiece, the contour of the mouthpiece fits securely into the teethand/or soft palate of the user, allowing the user to insert or removethe device as needed.

Another feature that is present in many embodiments in the use of anovel valve that does not appreciably impede air flow in a certaindirection (inspiration), and partially impedes air flow in the otherdirection (expiration). Moreover, the valvular mechanism in manyembodiments allows for the expiratory obstruction to be relieved if acertain degree of air flow or pressure differential across the device isachieved, as might be the case with coughing. For example, in someembodiments, the valve flap is made of a shape memory material that isbendable; when the pressure differential across the valve or expiratoryair flow is large enough, the flap bends upon itself thereby relievingthe obstruction. This is important during coughing and also facilitatesthe clearance of mucous and other substances during coughing. After thecough, the flap returns to its original, non-bent conformation.

In certain embodiments, the subject devices include a shape memoryelement or elements, both for use in anchoring the device within thebody or in the valvular mechanism itself. Any convenient shape memorymaterial which provides for the requisite features of flexibility andresumption of configuration following removal of applied force may beemployed in these embodiments. As such, shape memory alloys find use. Avariety of shape memory alloys are known, including those described inU.S. Pat. Nos. 5,876,434; 5,797,920; 5,782,896; 5,763,979; 5,562,641;5,459,544; 5,415,660; 5,092,781; 4,984,581; the disclosures of which areherein incorporated by reference. The shape memory alloy that isemployed should generally be a biocompatible alloy. Specificbiocompatible alloys that find use include those nickel-titanium (NiTi)shape memory alloys sold under the Nitinol™ name by Memry Corporation(Brookfield, Conn.). Also of interest are spring steel and shape memorypolymeric or plastic materials, where such materials includepolypropylene, polyethylene, etc.

The subject devices may be manufactured using any convenient protocol,where suitable protocols are known in the art. Representativemanufacturing methods that may be employed include machining, and thelike.

Turning now to the figures, FIG. 1 provides a three-dimensional view ofa first embodiment of the subject devices in which the device isimplantable, where the device is depicted in a first, retractedposition. The device shown in FIG. 1 has multiple anchoring members 20A,20B, 20C, and 20D. Located centrally to the anchoring members 20A, 20B,20C, and 20D, is a central rim 22. A planar element 24, fixed to thecentral rim 22, is connected to a movable element 26 by hinge joint 23to form a central valve 21. The entire device, in the retractedposition, is housed within a catheter 28 which allow the device to beplaced at the appropriate location within the respiratory tract prior todeployment.

FIG. 2 provides a three-dimensional view of the device shown in FIG. 1,where the device is depicted in the deployed position with closure ofthe central valve 21. Anchoring members 20A, 20B, 20C, and 20D are inthe deployed or non retracted position which allows the device to beanchored to the surrounding tissues (not shown). Moveable element 26 isin the closed position because of the flow of air from distal toproximal airways as might be expected during exhalation.

FIG. 3 provides a three-dimensional view of the device shown in FIG. 1,where the device is depicted in deployed position with complete openingof the central valve 21 in the downward direction. The moveable element26 pivots around the hinge joint 23 resulting in an opening through thecenter of the device. This pivoting is due to the flow of air from theproximal to distal airways as expected during inhalation. Fixed element24 does not move during this pivoting; it remains attached to rim 22.

FIG. 4 provides a three-dimensional view of the device shown in FIG. 1,where the device is depicted in a deployed position with deflection ofthe central valve 21 in the upwards direction for partial opening. Themoveable element 26 has been transiently bent by the large air flow fromthe distal to proximal airways at high pressure exceeding that of normalexpiration as might be expected during a cough. Moveable element 26returns to its position in FIGS. 2 and 3 during subsequent stages of theregulatory cycle.

FIG. 5 provides a three-dimensional view of a second embodiment of thesubject devices in which the device is removable and fits within theoral cavity. In this embodiment, indentations 30 and 32 are grooves inwhich the user's teeth and/or gums fit, serving as a means to secure thedevice within the oral cavity.

FIG. 6 provides a three-dimensional view of the device shown in FIG. 5,where the device is depicted during exhalation with closure of thevalve. Moveable element 36 is in the closed position and is attached tofixed element 34 via hinge 33. Fixed element 34 is also permanentlyattached to rim 38.

FIG. 7 provides a three-dimensional view of the device shown in FIG. 5,where the device is depicted during inhalation with inward opening ofthe valve, with inward opening of the moveable element 36.

FIG. 8 provides a three-dimensional view of the device shown in FIG. 5,where the device is depicted with outward deflection of the valve. Thismight occur during a cough, during which moveable element 36 bendsoutward in response to increased air flow and/or increase pressuregradient across the length of the device.

FIGS. 9-12 provide more detailed views of the operation of the valve 21.The moveable element 26 is hingedly coupled to the fixed element 24 by ahinge pin 25. The moveable element 26 further has a cam surface 27permitting the moveable element 26 to freely move in the direction ofarrow 100 during inspiration. This condition of the valve 21 is shown inFIG. 11. During normal expiration, the moveable element 26 returns tothe closed position illustrated in FIG. 10.

During expiration at high pressure, such as during a cough, the hingedend of the moveable element 26 remains fixed due to the earn surface 27.However, the moveable element 26 is permitted to flex along its lengthas shown in FIG. 12 to partially open. After the cough subsides, themoveable element 26 then returns to a condition commensurate with theinspiration or normal expiration of the patient.

Hence, the valve provides a first flow resistance to airflow fromproximal airways to distal airways (inhalation) and a second flowresistance to normal expiration air flow from distal airways to proximalairways. In addition, the valve further provides a third flow resistanceto high pressure expiration air flow from distal airways to proximalairways. The first airflow resistance is less than the third air flowresistance and the third air flow resistance is less than the secondairflow resistance. As a result, normal inspiration, normal expiration,and high pressure expiration are accommodated while maintainingimprovement in the breathing of the patient.

Utility

The subject methods and devices find use with a variety of differenttypes of animals. Representative animals with which the subject methodsand devices find use include, but are not limited to: canines; felines;equines; bovines; ovines; etc. and primates, particularly humans.

Kits

Also provided are kits that at least include the subject devices. Thesubject kits at least include a device of the subject invention andinstructions for how to use the device in a procedure. The instructionsare generally recorded on a suitable recording medium. For example, theinstructions may be printed on a substrate, such as paper or plastic,etc. As such, the instructions may be present in the kits as a packageinsert, in the labeling of the container of the kit or componentsthereof (i.e., associated with the packaging or subpackaging) etc. Inother embodiments, the instructions are present as an electronic storagedata file present on a suitable computer readable storage medium, e.g.,CD-ROM, diskette, etc. The instructions may take any form, includingcomplete instructions for how to use the device or as a website addresswith which instructions posted on the world wide web may be accessed.

The following examples are offered by way of illustration and not by wayof limitation.

EXPERIMENTAL I. Use of the Device A. Implantable Application:

Using standard visualization techniques including but not limited toflexible and rigid bronchoscopy, laryngoscopy, fluoroscopy, and directvision (as in open surgery), a catheter or other similar device capableof housing the device is directed to appropriate site within thepulmonary tree (trachea, bronchi, or bronchioles). The device shown inFIG. 1 shows the retracted (more compact) version of the device whichfits within the distal segment of the catheter or housing. At theappropriate site, the device is released, most likely using a plunger tokeep the device stationary as the protective housing is advancedproximally. Once out of the housing, the anchoring elements 20A, 20B,20C, 20C, and 20D spring to their preferred shape. This preferred shapeis one in which the anchoring elements are positioned away from eachother and are in contact with the respiratory conduit, thus securing thedevice in place.

Once deployed, the device works as follows. During inspiration, thedevice remains in the open position. Open position means the moveableelement 26 has pivoted around hinge 23 towards the direction of thedistal airways. This pivoting action is the result of the airflow fromthe proximal to distal airways. During exhalation, the airflow from thedistal airways to the proximal airwlays results in the moveable element26 pivoting in the opposite direction to a closed position in which themoveable element 26 is adjacent to rim 22. This creates the requisiteexpiratory obstruction. During a cough, the significantly increased flowof air from the distal to the proximal airways causes the moveableelement 26 to deflect upon itself with no additional pivoting aroundhinge 23 as compared to normal exhalation. This mechanism serves torelieve the expiratory obstruction and promotes clearance of secretionand debris.

B. Removable Application:

The device shown in FIGS. 5 and 6 is placed into the subject's mouth bymedical personnel or by the subject himself where it is kept in place bythe subject's teeth and shape of the oral cavity. The device can be wornat night, during the day, or both.

Once in place, the device works as follows. During inspiration, thedevice remains in the open position. Open position means the moveableelement 36 has pivoted around hinge 33 towards the direction of thedistal airways. This pivoting action is the result of the airflow fromthe proximal to distal airways. During exhalation, the airflow from thedistal airways to the proximal airways results in the moveable element36 pivoting in the opposite direction to a closed position in which themoveable element 36 is adjacent to rim 38. This creates the requisiteexpiratory obstruction. During a cough, the significantly increased flowof air from the distal to the proximal airways causes the moveableelement 36 to deflect upon itself with no additional pivoting aroundhinge 33 as compared to normal exhalation. This mechanism serves torelieve the expiratory obstruction and promotes clearance of secretionand debris.

It is evident that the subject devices provide a number of importantadvantages over prior art devices. The subject devices improve thebreathing of the patient by mimicking the effects of pursed-lipbreathing which is adopted instinctively by affected patients.Physiologically, it is anticipated that the beneficial effects of thedevice will be the same as those experienced in pursed-lip breathing,specifically improving oxygen saturation, decreasing respiratory rate,and increasing tidal volume. This in turn will reduce the probability ofthe affected patient developing pulmonary hypertension, right-sidedheart failure and other sequelae secondary to chronic obstructivepulmonary disease. Furthermore, the devices offer the significantadvantage of freeing the patient from constantly pursing his lips, whichis a conscious action. Moreover, in contrast to pursed-lip breathingwhich requires conscious effort and cannot be performed during sleep,these devices allow pursed-lip breathing throughout the day. As such,the subject invention represents a significant contribution to the art.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

1. A method of treating a subject with a removable device that may beapplied and removed by the subject, the method comprising: removablysecuring the device so that the subject may breathe through the device;moving a movable element during inspiration to an open position to allowairflow through the device; and moving the movable element to at least apartially closed position during exhalation to create a resistance toairflow through the device.
 2. The method of claim 1, wherein securingthe device comprises securing the device to the subject's face.
 3. Themethod of claim 1, wherein securing the device comprises securing thedevice in the subject's mouth.
 4. The method of claim 1, furthercomprising instructing the subject to wear the device while sleeping. 5.The method of claim 1, further comprising instructing the subject toremove the device.
 6. The method of claim 1, wherein moving a movableelement during inspiration comprises opening a flap valve.
 7. The methodof claim 1, wherein moving the movable element to at least partiallyclosed position during exhalation comprises creating a resistance toairflow through the device during exhalation that is greater than theresistance during inspiration.
 8. A method of treating a subject with aremovable device that may be applied and removed by the subject, themethod comprising: removably securing the device so that the subject maybreathe through the device while sleeping; moving a movable elementduring inspiration to an open position to allow airflow through thedevice at a first flow resistance; and moving the movable element to atleast a partially closed position during exhalation to create a secondflow resistance that is greater than the first flow resistance.
 9. Themethod of claim 8, wherein securing the device comprises securing thedevice to the subject's face.
 10. The method of claim 8, whereinsecuring the device comprises securing the device in the subject'smouth.
 11. The method of claim 8, further comprising instructing thesubject to wear the device while sleeping.
 12. The method of claim 8,further comprising instructing the subject to remove the device.
 13. Themethod of claim 8, wherein moving a movable element during inspirationcomprises opening a flap valve.
 14. A method of treating a subject witha removable device that may be applied and removed by the subject, themethod comprising: providing the removable device to the subject,wherein the removable device comprises a movable element configured tobe displaced during inspiration to open the device and allow airflowthrough the device, wherein the movable element is further configured toat least partially close the device during exhalation to create aresistance to airflow through the device; and instructing the subject toapply the device so that the subject may breathe through the devicewhile sleeping.
 15. The method of claim 14, further comprisinginstructing the subject to sleep while wearing the device.
 16. Themethod of claim 14, further comprising instructing the subject to removethe device.
 17. The method of claim 14, wherein instructing the subjectto apply the device comprises instructing the subject to secure thedevice to the face.
 18. The method of claim 14, wherein instructing thesubject to apply the device comprises instructing the subject to securethe device in the mouth.